InterSV - Structure Variant Interpretation
ACMG introduces a quantitative, evidence-based scoring framework; encourages the implementation of the five-tier classification system widely used in sequence variant classification; and recommends "uncoupling" the evidence based classification of a variant from its potential implications for a particular individual.The ACMG professional standards will guide the evaluation of constitutional CNVs and encourage consistency and transparency across clinical laboratories. We aligned and extended these ACMG/AMP/ClinGen guidelines for structure variants(SVs). The evidence category include: 1.Initial assessment of genomic content;2.Established (or Predicted) Pathogenic or Benign Dosage Sensitive Genes/Genomic Regions;3.Evaluation of Gene Number;4.Detailed Evaluation of Genomic Content Using Cases from Published Literature, Public Databases;5.Evaluation of Inheritance Pattern/Family History.
The standards build by introducing a semiquantitative point-based scoring metric for classification. In general,scores for each observed piece of evidence, both in support of (positive values) and refuting (negative values) pathogenicity, are summed to arrive at a final classification. SVs with a final point value >=0.99 are considered pathogenic, while point values between 0.90 and 0.98 are consided likely pathogenic; The variant of uncertain significance (VUS) category is the broadest, corresponding to points between −0.89 a 0.89 ,while refutinnng evidence arriving at scores between −0.9 and 0, <=-0.90 are considered likely benign and benign, respectively.